Inclusion Criteria:
Individuals must meet all of the following criteria to be included in the study:
1. Have read, understood, and signed the Informed Consent Form (ICF).
2. Male or female aged greater than or equal to (\>=) 18 years at the time of signing the ICF.
3. Histologically or cytologically confirmed carcinoma of the colon and/or rectum deemed unresectable and/or with evidence of metastases, that has been cytologically or genetically confirmed as dMMR, and/or MSI-H.
4. Demonstrated disease progression and/or intolerability to prior treatment with any of the following: pembrolizumab, nivolumab (±ipilimumab), dostarlimab, chemotherapy (ie, FOLFOX, FOLFIRI, CAPEOX, or FOLFOXIRI \[±bevacizumab\]), encorafenib/cetuximab, trastuzumab-based combinations, KRAS inhibitor/EGFR inhibitor, regorafenib, or TAS-102 (±bevacizumab)
5. Measurable disease according to RECIST version 1.1.
6. Adequate organ function:
1. Absolute neutrophil count \>=1,500 cells per/μL
2. Platelets \>=100,000 cells/μL
3. Hemoglobin \>=9 grams per deciliter (g/dL)
4. Total bilirubin less than or equal to (\<=) 1.5\*the Upper Limit of Normal (ULN) (\<=3\*ULN if attributable to known Gilbert's syndrome)
5. Aspartate Aminotransferase (AST)/Alanine Aminotransferase (ALT) \<=5\*ULN if liver metastasis present; if liver metastasis is not present, then AST/ALT \<=3\*ULN.
7. Measured creatinine clearance \>=60 milliliter per minute (mL/min) per Cockcroft-Gault formula.
8. Prothrombin time (PT) or international normalized ratio and Partial Thromboplastin Time (PTT) \<=1.5\*ULN, unless receiving anti-coagulant therapy; Note: activated PTT can be used instead of PTT if it is the site's standard practice.
9. Have agreed to tissue sampling (biopsy \[if available\], baseline archival tissue, and/or fresh frozen tissue \[if available\]).
10. Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1.
11. An estimated life expectancy of at least 3 months based on investigator judgment.
12. Women of childbearing potential (WOCBP) and men must agree to use 2 highly effective methods of contraception or practice abstinence from 4 weeks before the first dose of DES-1357, throughout the study, and for 6 months after the last dose of DES-1357; men must refrain from donating or banking sperm during the same period.
13. Negative serum pregnancy test result at screening and on Cycle 1 Day 1 for WOCBP.
14. Female participants who are not WOCBP should meet at least 1 of the following criteria:
have undergone a documented hysterectomy, bilateral oophorectomy and/or bilateral salpingectomy; have medically confirmed ovarian failure, or achieved postmenopausal status (defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause, or have a serum follicle-stimulating hormone level within the laboratory's reference range for postmenopausal women).
Exclusion Criteria:
Individuals meeting any of the following criteria at screening or baseline are ineligible to participate in this study:
1. Cytologically and/or genetically confirmed proficient mismatch repair (pMMR) and/or MSS.
2. Evidence of severe gastrointestinal malabsorption as determined by the investigator.
3. History or presence of dysphagia.
4. Symptomatic or clinically significant bowel obstruction, perforation, or high risk for obstruction as determined by the investigator.
5. Hypersensitivity to any component of DES-1357.
6. Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) greater than (\>) 470 milliseconds (msec) based on triplicate 12-lead ECGs obtained at screening.
7. Has an active infection.
8. Has known Human Immunodeficiency Virus (HIV) infection that is not under control. All of these criteria are required: undetectable viral RNA, CD4+ counts/levels \>=350, no history of Acquired Immune Deficiency Syndrome (AIDS)-defining opportunistic infection within the past 12 months, and clinically stable for at least 3 months on the same anti-HIV medications.
9. Has active or uncontrolled hepatitis B or C infection. Participants are eligible if they:
1. Have been curatively treated for hepatitis C virus infection as demonstrated clinically and by viral serologies
2. For hepatitis B, if the participant has a positive hepatitis B surface antigen result, viral load must be below 2000 international units per milliliter (IU/mL) in the absence of antiviral therapy for the last 12 weeks, and AST/ALT \<=3\*ULN
10. Uncontrolled diabetes as determined by the investigator.
11. Cardiovascular and/or cerebrovascular event in the prior 6 months before screening.
12. Has received prior treatment with a Werner Syndrome Helicase (WRN) inhibitor.
13. Has been diagnosed with Werner Syndrome.
14. Primary Central Nervous System (CNS) tumor/CNS metastasis.
15. Ongoing toxicities from prior anti-cancer therapy that have not resolved to baseline or grade \<=1 (according to NCI-CTCAE version 6.0), except for alopecia and endocrinopathies that are stable under medication.
16. Is pregnant or breastfeeding, is planning to become pregnant during the study.
17. Is planning to donate/bank or retrieve eggs (ova, oocytes) or donate sperm during the study.
